Treatment of iron-deficiency anemia typically employs oral administration of an iron preparation, but sometimes the administration is not done orally but non-orally: when a large volume of iron has to be administered; when an orally-administered iron preparation cannot be properly absorbed; when a patient experiences side effects from oral administration of such preparations; and when iron loss due to chronic, sustained hemorrhage is greater than iron absorption resulting in loss of stored iron.
When an iron preparation is administered orally, the rate of its absorption through the intestinal canals depends on the concentration of free iron; and accordingly, free iron has a higher therapeutic effect. For this reason, a ferrous preparation which can exist as free iron in high concentration is more often used for therapeutic purposes.
Depending upon dosage, non-oral administration of free iron can bring a living thing to which it has been administered to an extremely dangerous state. Thus, strenuous efforts are being made to manufacture iron preparations with a low content of free iron. Unlike oral iron preparations, non-oral iron preparations have to meet basically different requirements: namely, adequate molecular weight; minor excretion in urine; high concentration of iron; easy availability of injection liquid, which is isotonic with the body fluid; stability of solution around neutrality; and stable storability as a solution. Thus, the non-oral iron preparations require more demanding manufacturing techniques than the oral ones to assure safety and stability.
Several patents disclose the effectiveness of complexes composed of a ferric salt, a mono- or oligosaccharide and a hydroxycarboxylic acid for treatment of iron-deficiency anemia. For example, Japanese Patent Publication Nos. SHO 40-7296 and SHO 40-17782 disclose a method of obtaining an iron preparation by reacting a ferric salt, hexytol and a mono-, di- or tribasic hydroxycarboxylic acid in the presence of a dispersion-stabilizer. This method, however, can produce only a preparation with a relatively low iron content of 15-16%; and when injected into the veins of a mouse, the preparation produces high toxicity value of LD.sub.50 of 35 mg/kg.
Japanese Patent Publication No. SHO 46-3196 discloses a method of obtaining an iron preparation by reacting one mole of ferric hydroxide with two moles of a complex-forming agent composed of about 1.5 mole of sorbitol, about 0.4 mole of gluconic acid and 0.5 mole (as glucose) of dextrin with mean molecular weight between 500 and 1200, dextran, hydrogenated dextrin or hydrogenated dextran. The resulting iron preparation also has a low iron content between 21 and 26%. When administered to a human being, 10% of the iron administered is excreted in urine; and the value of LD.sub.50, when intramuscularly injected into a mouse, is 380 mg/kg which means relatively high toxicity.
These saccharide-hydroxycarboxylic-ferric complexes also have the following drawbacks: with relatively low molecular weight, the complexes are likely to damage blood corpuscle, blood vessel and muscle; and solutions of the complex can be stable only at pH values far higher than those of blood and body fluid. Thus, those complexes are not useful as iron preparations that can be administered non-orally.
In the case of dextran-ferric complex, which has been available as an iron preparation for non-oral administration, it is extremely slow to decompose within an animal body. Dextran is cumulative, and when administered nonorally, it is poorly taken into the reticuloendothelial system of the body. Dextran accumulates in the blood, acts as an antigen, yielding an anti-body, and is reported as carcinogenic. Moreover, dextran is expensive. Thus it is controversial in non-oral applications.
In the case of dextrin-ferric complex, dextrin, unlike dextran, is not cumulative on account of metabolizing enzymes being present in the body, and it does not yield harmful antibodies. Having a high molecular weight, the dextrin-ferric complex is not filtered off by the kidney and is excreted in a minor amount as urine. Dextrin, however, contains a reducing group which can yield a free ferrous ion by reducing a ferric compound to a ferrous one. Moreover, the dextrin-ferric complex in a liquid phase lacks stability during prolonged storage and lacks thermal stability.
The present inventors attempted to improve the stability of iron preparations using high molecular weight dextrin, but failed to attain such a result. Only preparations having a poor curative effect and a low iron content were obtained. The manufacture of a dextrin-ferric complex having an increased iron content, having a decreased effect of the reducing group in dextrin and having a yield substantially free of ferrous ion, was tried. That resulted in an unstable complex with a decreased water retention.